Journal
EMBO MOLECULAR MEDICINE
Volume 11, Issue 11, Pages -Publisher
WILEY
DOI: 10.15252/emmm.201910469
Keywords
caloric restriction; caloric restriction mimetic; cardioprotection; TFE3; TFEB
Categories
Funding
- Ligue contre le Cancer (equipe labelisee)
- Agence National de la Recherche (ANR)-Projets blancs
- ANR under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases
- Association pour la recherche sur le cancer (ARC)
- Canceropole Ile-de-France
- Institut National du Cancer (INCa)
- Fondation de France
- Fondation pour la Recherche Medicale (FRM)
- the European Commission (ArtForce)
- European Research Council (ERC)
- Institut Merieux, the LabEx Immuno-Oncology
- SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE)
- SIRIC Cancer Research and Personalized Medicine (CARPEM)
- Paris Alliance of Cancer Research Institutes (PACRI)
- Austrian Science Fund FWF (Austria) [P29262, P24381, P29203, P27893]
- SFB Lipotox [F3012]
- Bundesministerium fur Wissenschaft, Forschung und Wirtschaft
- Karl-Franzens University [W1226]
- NAWI Graz
- BioTechMed-Graz flagship project EPIAge
- Erasmus+ International mobility program
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Caloric restriction mimetics (CRMs) are natural or synthetic compounds that mimic the health-promoting and longevity-extending effects of caloric restriction. CRMs provoke the deacetylation of cellular proteins coupled to an increase in autophagic flux in the absence of toxicity. Here, we report the identification of a novel candidate CRM, namely 3,4-dimethoxychalcone (3,4-DC), among a library of polyphenols. When added to several different human cell lines, 3,4-DC induced the deacetylation of cytoplasmic proteins and stimulated autophagic flux. At difference with other well-characterized CRMs, 3,4-DC, however, required transcription factor EB (TFEB)- and E3 (TFE3)-dependent gene transcription and mRNA translation to trigger autophagy. 3,4-DC stimulated the translocation of TFEB and TFE3 into nuclei both in vitro and in vivo, in hepatocytes and cardiomyocytes. 3,4-DC induced autophagy in vitro and in mouse organs, mediated autophagy-dependent cardioprotective effects, and improved the efficacy of anticancer chemotherapy in vivo. Altogether, our results suggest that 3,4-DC is a novel CRM with a previously unrecognized mode of action.
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